A urea cycle disorder (UCD) is an inherited disease that affects how the body removes the waste that is made from breaking down protein. Everyone needs protein, which is found in foods like dairy products, meat and fish. When a person eats food that contains protein, the body breaks it down into amino acids (the building blocks of protein that are used by the body for growth and tissue repair) and uses only what it needs. It changes the rest into nitrogen, which must then be removed by the body as urea.

In a healthy person, the liver makes several enzymes to change nitrogen into urea, which is then removed from the body in urine. This process is called the urea cycle.

The liver in a person with urea cycle disorder is missing an enzyme necessary to convert nitrogen into urea. As a result, ammonia, a highly toxic substance, builds up in the bloodstream and is not removed from the body. Untreated, the high amounts of ammonia can cause brain damage, coma and eventually death.

Causes of UCD

Urea cycle disorders are named based on the initials of the missing enzyme. They are:

• OTC – ornithine transcarbamylase
• ASD – argininosuccinic acid synthetase (citrullinemia)
• AG – arginase
• ALD – argininosuccinase acid lyase (argininosuccinic aciduria)
• CPS – carbamoyl phosphate synthetase
• NAG – N-acetylglutamate synthetase.

Urea cycle disorders occur in about one in 35,000 newborns.

Urea cycle disorders are genetic. Genes give the body instructions on how to break down protein. We usually have two copies of each gene, and most UCDs only occur when a person inherits a changed gene from both parents. The exception is OTC deficiency, which is passed to the baby through the mother who is most often not affected.

If both parents carry the abnormal gene (not OTC deficiency), there is:

• A 25% chance that their child will develop the disorder.
• A 50% chance that their child will receive one defective gene from one of the parents, which means the child will not show symptoms of the disorder; the child is a "carrier" of UCD.
• A 25% chance that their child will receive both working genes, one from each parent, and will be unaffected.

With OTC deficiency, the risks that a person will be affected also depend on if they are male or female. If the mother carries the defective gene, there is:

• A 50% chance that a male child will receive the defective gene from the mother. The child will be affected by UCD.
• A 50% chance that a male child will receive the normal gene and be unaffected.
• A 50% chance that a female child will receive the abnormal gene, and be at risk of having symptoms related to OTC deficiency.
• A 50% chance that a female child will get the normal gene and be unaffected.

Signs and Symptoms of UCD

The age of onset and specific symptoms vary between the different types of UCD. This disorder is most often diagnosed in infancy. Some children do not show symptoms until early childhood.

In children with severe UCD, the symptoms will develop within the first 24 hours of life. Usually, the baby will become very sleepy and irritable and will have feeding problems, including poor feeding and vomiting. Seizures, trouble breathing and coma may appear later.

Symptoms in children with mild or moderate UCD, who do not show symptoms until early childhood, may include:

• Disliking meat or other foods rich in protein
• Vomiting, nausea
• Confusion or hyperactive behavior
• Often tired, hard to wake up
• Coma

Diagnosis of UCD

The diagnosis is made by analysis of the urine and blood for abnormal metabolites (substance produced by metabolism), and high ammonia levels.

A liver biopsy can be done to identify the type of UCD. This test will highlight the genetic changes that cause the UCD. A liver biopsy can be done to confirm the diagnosis, since it can show low levels of enzyme activity. A liver biopsy is not done regularly.

An MRI or CT scan may be done to see if there is swelling of the brain caused by the ammonia in the blood.

Treatment for UCD

Treatment is a lifelong process that doesn't cure the condition, but it can effectively manage the symptoms. Frequent blood tests are done to monitor ammonia levels. Doctors in the areas of pediatrics, genetics and nutrition will work together to develop the child's treatment plan.

The child's treatment could involve:

• A low protein, high-calorie diet. Protein in the diet is lowered by avoiding protein-rich foods. Examples of foods that provide calories without loading the body with protein are fruits, vegetables and starches. Protein restriction must be done with advice from a healthcare professional. A dietitian will plan and update a protein-restricted diet as the child grows. Some children need to take a special formula to make sure they are getting proper nutrition.
• Medications. Some children will need to take medicine to help get extra ammonia out of their body. Medication by mouth is given that binds to ammonia and carries it out in the urine.
• Amino acid supplements. Depending on the type of UCD, amino acid supplements such as arginine or citrulline may be added to the diet. This helps give the body what it needs to make proteins that are important for growth and tissue repair, since children with UCD can't make arginine on their own.
• Liver transplantation. Because the production of urea cycle enzymes takes place in the liver, a liver transplant can be an effective treatment for urea cycle disorder.

Your doctor will talk to you about the risks of transplantation. If a transplant is the best treatment option, your doctor and members of the care team will focus on preventing complications. The care team will treat symptoms while your child waits for the donated liver.

Illness, fever, surgery or an accident, can cause ammonia levels to rise. Care must be taken at these times. Extra calories will be needed to provide the stressed body with fuel.

Visits with your doctors and other specialists will be needed to make adjustments to diet and medication. Having your child follow the diet your doctor gives is important for your child's health, growth and development.

Long-Term Outlook

There currently is no cure for urea cycle disorders. However, there are some clinical trials for certain UCD. Ask your geneticist about clinical trials for your child’s UCD. Outcomes depend on the type of UCD, how severe it is, how early it is diagnosed and how closely the treatment plan and diet are followed.

Early diagnosis and treatment are needed for children to have a chance for good results. Babies who are diagnosed in the first week of life and are put on a diet right away may do well. If your child continues to carefully follow the diet, normal brain function can be reached.

If the child does not follow the diet or if the child has stress-induced symptoms, this can lead to repeated brain swelling and irreversible brain damage.

Transplants have been effective in reversing the symptoms of urea cycle disorder.